Alu elements mediate large SPG11 gene rearrangements: further spatacsin mutations

• Published in: Genetics in medicine Vol. 14; no. 1; pp. 143 - 151
• Main Authors: Conceição Pereira, Maria, Loureiro, José Leal, Pinto-Basto, Jorge, Brandão, Eva, Margarida Lopes, Ana, Neves, Georgina, Dias, Pureza, Geraldes, Ruth, Martins, Isabel Pavão, Cruz, Vitor Tedim, Kamsteeg, Erik-Jan, Brunner, Han G., Coutinho, Paula, Sequeiros, Jorge, Alonso, Isabel
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 2012; Elsevier Limited
• Subjects: 631/208/737; 631/337/1427/2190; 692/699/375/365; Adolescent; Adult; Alleles; Alu Elements; Amino Acid Sequence; Base Sequence; Biomedical and Life Sciences; Biomedicine; Child; Child, Preschool; Chromosome Breakpoints; Exons; Female; Gene Order; Genotype; Human Genetics; Humans; Infant; Laboratory Medicine; Male; Middle Aged; Molecular Sequence Data; Mutation; original-research-article; Paralysis; Pedigree; Proteins - genetics; Sequence Deletion; Spastic Paraplegia, Hereditary - genetics; Spasticity; Young Adult; hereditary spastic paraplegia; large gene rearrangements, spatacsin; mediated nonallelic homologous recombination
• DOI: 10.1038/gim.2011.7
• ISSN: 1098-3600

Purpose: Hereditary spastic paraplegias compose a group of neurodegenerative disorders with a large clinical and genetic heterogeneity. Among the autosomal recessive forms, spastic paraplegia type 11 is the most common. Methods: To better understand the spastic paraplegia type 11 mutation spectrum, we studied a group of 54 patients with hereditary spastic paraplegia. Mutation screening was performed by PCR amplification of SPG11 coding regions and intron boundaries, followed by sequencing. For the detection of large gene rearrangements, we performed multiplex ligation-dependent probe amplification. Results: We report 13 families with spastic paraplegia type 11 carrying either novel or previously identified mutations. We describe a complex entire SPG11 rearrangement and show that large gene rearrangements are frequent among patients with spastic paraplegia type 11. Moreover, we mapped the deletion breakpoints of three different large SPG11 deletions and provide evidence for Alu microhomology-mediated exon deletion. Conclusion: Our analysis shows that the high number of repeated elements in SPG11 together with the presence of recombination hotspots and the high intrinsic instability of the 15q locus all contribute toward making this genomic region more prone to large gene rearrangements. These findings enlarge the amount of data relating repeated elements with neurodegenerative disorders and highlight their importance in human disease and genome evolution. Genet Med 2012:14(1):143–151